The invention relates to the preparation of 24-alkyl analogs of cholecalciferol, new intermediates and new non-racemic compounds being valuable synthones for the synthesis of pharmacologically active substances.
In particular the invention relates to the preparation of synthetic analog of vitamin D3-calcipotriol, biologically active compound used in medical treatment.
Calcipotriol, ie. 1α,3β,5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol, alike natural metabolits of vitamin D3, such as 1α,24R-dihydroxycholecalciferol (tacalcitol) and 1,25-dihydroxycholecalciferol (calcitriol), exhibits activity inhibiting undesirable proliferation of epidermal keratinocites [F. A. C. M. Castelijins, M. J. Gerritsen, I. M. J. J. van Vlijmen-Willems, P. J. van Erp, P. C. M. van de Kerkhof; Acta Derm. Venereol. 79, 111 (1999)].
Preparation of calcipotriol has been disclosed in an International Patent Application WO 8700834, as well as in the publication M. J. Calverley, Tetrahedron 43, 4609 (1987). The described method relies on adding side chain C(23)-C(27) to a protected C(22)-aldehyde derivative of (5E)-cholecalciferol, in a Wittig type reaction with (cyclopropyl)carbonylmethylene triphenylphosphate. The C(24)-ketone group is then reduced, giving a mixture of C(24)-epimeric alcohols, which are separated by chromatography to remove the undesirable isomer (24R). Isomer (5E),(24S) is further subjected to a photoisomerization to give isomer (5Z),(24S). In the last step of the synthesis, the silyl protecting groups at C(1)-OH and C(3)-OH are removed to give calcipotriol. Similarly, photoisomerization and deprotection of hydroxyl of the isomer (5E),(24R) gives the (24R)-analog of calcypotriol.
A different method for preparation of calcipotriol (M. J. Calverley, Synlett 157, 1990) consists in condensing protected C(22)-diseleneacetal, a derivative of (5E)-cholecalciferol, with (S)-2-[(t-butyl)dimethyl]silyloxy-2-cyclopropylacetate aldehyde. A mixture of diastereoisomeric 23-hydroxy-22-methylselenide thus obtained is treated with methanesulfonic chloride in the presence of triethylamine, to give a compound of the proper configuration (24S), being however a mixture of (22E) and (22Z) olefins. The mixture of (5E),(22E/Z) olefins requires further chromatographic separation and a photoisomerisation to give the compound of (5Z),(22E) configuration. After removing of silyl groups at C(1), C(3) and C(24), calcipotriol is obtained.
Yet another method for preparation of a mixture of C924)-epimers of calcipotriol, described in the Japanese Patent Application JP 08325226 A2, includes coupling of ring A of calcipotriol, that is (4R,6S)-4,6-di(t-butyl)dimethylsilyloxy-7-octen-1-yn, with 7-bromo-derivative formed by CD rings of calcipotriol in a Heck-type reaction, followed by deprotection. It is a multi-step and time-consuming process.
The synthesis of the (7Z)-calcipotriol isomer from a substituted cholesta-5,7-diene by a photochemical transformation or a thermal rearrangement is disclosed in Japanese Patent Application JP 06316558 A2.
All mentioned above methods for preparation of alkyl analogues of cholecalciferol exhibit the following disadvantages: a) tendency to isomerization of asymmetric center at C(20) in the C(22)-aldehyde derivatives of cholecalciferol used as the substrates, b) lack of proper stereoselectivity at the step of C(24)-ketone reduction, c) a need for repeated chromatography, d) use of very unstable derivative of toxic methylselenol, e) lack of stereoselectivity at the step of removing selenium from (-hydroxy)methylselenides, and/or f) the use of difficult to obtain CD ring synthon of calcipotriol. All these factors constitute a serious limitation of the practical value of these methods.
Thus, a new method of synthesis of biologically active 24-alkyl analogs of vitamin D had to be developed that would be effective, short and convenient, making use of available vitamin D derivatives and not requiring the use of very toxic reagents.